Anticoagulant-related gastrointestinal bleeding: a real-life data analysis on bleeding profiles, frequency and etiology of patients receiving direct oral anticoagulants versus vitamin K antagonists.

Vitamin K antagonists (VKA) continue to be the standard of long-term anticoagulation. Direct oral anticoagulants(DOAC) are increasingly used. In many trials DOAC were at least as effective as VKA. In this study we evaluate the bleeding profiles, frequencies and etiologies of patients receiving DOAC versus VKA in a real-life setting. All patients presenting with suspected gastrointestinal bleeding (GIB) in the emergency department of the University Hospital Erlangen in one year were enrolled in this study. They were looked up for the intake of either DOAC (dabigatran, rivaroxaban and apixaban) or VKA. The results showed that 406 patients with suspected GIB were admitted to the emergency unit of the University Hospital Erlangen. In 228 of those patients GIB could be verified (56.2%). Fifty four of those patients (23.7%) were administered either VKA or DOAC. In 35 of those 54 patients (64.8%) GIB was classified as 'major bleeding'. In 27 patients with administration of VKA upper GIB was recorded and lower GIB was detected four times. In 16 patients with administration of DOAC upper GIB was found and lower GIB was found in 7 patients. The presented data do not show higher GIB rates for DOAC (mainly dabigatran and rivaroxaban), but do also not indicate a significantly higher safety of DOAC concerning GIB than VKA. This finding represents a clear contrast to the reduced bleeding rates of DOAC for intracerebral bleeding and other non-GIB events. According to our study, the absolute number of DOAC-associated GIB events is lower than in the VKA group.

Esmolol for the control of hypertension after neurologic surgery.

We sought to evaluate the effectiveness of esmolol vs placebo in 40 patients emerging from general anesthesia for neurosurgery. Efficacy was defined as a decrease in systolic blood pressure to within 20% above average ward pressure. The need for additional antihypertensive agents to control blood pressure was also used to define efficacy. During the infusion period 20 of 21 (95%) of the esmolol-treated patients and two of 19 (11%) of the patients receiving placebo had return of systolic blood pressure to within 20% of average ward pressure (p less than 0.001). One out of 21 (5%) esmolol-treated patients and 14 of 19 (74%) of the placebo group required intervention with additional antihypertensive medications (p less than 0.001). Esmolol was found to be effective in controlling hypertension that develops on emergence from general anesthesia in patients undergoing neurosurgery.

A pharmacokinetic study of roxatidine acetate in chronic renal failure.

The pharmacokinetics of a single oral dose of roxatidine acetate 150 mg were studied in 31 patients with varying degrees of chronic renal failure. The patients were divided into 5 groups according to their creatinine clearance (Clcr): controls (Clcr 94.5 +/- 13.9 ml/min; n = 6); mild chronic renal failure (Clcr 47 +/- 6 ml/min; n = 4); moderate chronic renal failure (Clcr 27.3 +/- 3.1 ml/min; n = 4); severe chronic renal failure (Clcr 12.8 +/- 1.4 ml/min; n = 5) and uraemia (Clcr 6.6 +/- 0.6 ml/min; n = 12). Serum and urine samples were analysed with capillary gas chromatography to measure the salt of the desacetyl metabolite of roxatidine acetate (roxatidine). The terminal half-life was 6.02 +/- 0.31 hours in controls and 7.35 +/- 0.57, 9.3 +/- 0.83, 14.6 +/- 3.7 and 18.10 +/- 2.77 hours, respectively, in the 4 other groups, with progressively decreasing creatinine clearance. Maximum serum concentration and time to maximum serum concentration rose from 816 +/- 75 ng/ml and 2.08 +/- 0.22 hours, respectively, in controls to 1364.7 +/- 156 ng/ml and 4.05 +/- 0.47 hours, respectively, in uraemic patients. Relative total clearance progressively decreased with decreasing glomerular filtration rate (GFR) [from 353.6 +/- 26 ml/min in controls to 90.31 +/- 12.2 ml/min in patients with uraemia]. Renal clearance decreased from a control of 243.9 +/- 56 ml/min to 12.32 +/- 0.18 ml/min in uraemic patients. A linear correlation between creatinine clearance and both relative total clearance and renal drug clearance was noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Cefodizime in serum and skin blister fluid after single intravenous and intramuscular doses in healthy volunteers.

In gonorrhea therapy, cephalosporins are conventionally administered by intramuscular (i.m.) injection, which rather frequently leads to local side effects. To investigate whether the well-tolerated intravenous (i.v.) injection of cephalosporins may be of comparable gonocidal effect, levels of cefodizime, a new broad-spectrum cephalosporin, in serum and tissue fluid (suction blister and cantharides blister fluid) were determined in six healthy men. Single doses of 1 g of cefodizime were injected i.v. and i.m. according to a randomized crossover design. On i.m. injection the drug was completely bioavailable, and the peak concentration in serum was 75 +/- 8 micrograms/ml. The terminal half-life of serum levels was 2.4 h. Cefodizime concentrations in the blister fluids increased for 1.5 to 3 h after the i.v. dose and for at least 3 h on i.m. administration. The concentrations of non-protein-bound cefodizime in blister fluid already exceeded the MIC for 90% of Neisseria gonorrhoeae strains 10 min after i.v. injection and 20 to 30 min after the i.m. dose. At 6 h after each dose, active concentrations were still present in serum. The results suggest that cefodizime administered i.v. and i.m. has equivalent high cure rates in uncomplicated gonorrhea. This hypothesis should be tested further by a controlled clinical trial. If equivalent, i.v. administration excels because it is better tolerated locally.

Pharmacokinetics of cefpirome (HR 810), a new cephalosporin derivative administered intramuscularly and intravenously to healthy volunteers.

The pharmacokinetics of cefpirome (HR 810)3-(2,3-cyclopenteno-1-pyridinium)-methyl-7-2-synmethoximino -2-(2- aminothiazol-4-yl)-acetamido-ceph-3-em-4-carboxylate, a new cephalosporin with an extremely broad antimicrobial spectrum, were tested in an open cross-over trial in ten healthy male volunteers using i.v. and i.m. injections of 1 g. Serum concentrations were monitored over 24 h after application, using both chromatographic and microbiological assays. Urine was collected in 2-h fractions for up to 8 h after application, then for 4 h, and thereafter in 12-h fractions for up to 48 h after application. Urine concentrations of the drug were measured by both HPLC and bioassay. The measurements were compared by linear distribution independent regression, and were found to be equivalent, indicating no major antimicrobially active metabolites of HR 810. A two-compartment open model was used for the calculation of pharmacokinetic parameters for both i.v. and i.m. dosing. The median maximum concentration in plasma after i.m. administration was 30.6 mg/l at 1.6 h (HPLC). The elimination half-life times of 1.9 h to 2.1 h did not differ significantly between the two routes investigated. With regard to bioavailability there was no difference between the i.m. and i.v. routes, as demonstrated by the AUC and urinary recovery of unchanged substance. Clinically relevant urine concentrations of cefpirome were detected for at least 12 h after dosing. The general tolerability was good.

Single and multiple dose pharmacokinetics of intravenous cefpirome (HR 810), a novel cephalosporin derivative.

After intravenous injection of single doses of 1.0 g of cefpirome (HR 810) and multiple doses of 1.0 g b.i.d. for five days to the same ten healthy male volunteers in an open design, concentrations of unchanged drug were estimated at various times in serum and urine, over 24 h and 48 h, respectively. Cefpirome concentrations were determined using both high pressure liquid chromatography (HPLC) and a microbiological assay. The measurements obtained were compared by linear distribution independent regression, and were found to be equivalent, indicating no major antimicrobially active metabolites of cefpirome. Biological half-life (t1/2,beta) was determined by fitting a two-compartment open model to the data: t1/2,beta was 2 h (HPLC, median values). During the multiple dose phase of cefpirome (1.0 g b.i.d.) no accumulation of the serum levels could be detected with this dosage regimen. Urinary concentrations of unchanged cefpirome remained clearly above the minimal inhibitory concentration for Escherichia coli (0.03 mg/l) for about 36 h (microbiological assay). The general tolerance was good.

Dose linearity testing of intravenous cefpirome (HR 810), a novel cephalosporin derivate.

After intravenous injection of single doses of 0.25, 0.5, 1.0, 1.5 and 2.0 g of cefpirome (HR 810) to 46 healthy male volunteers in an open manner, concentrations of unchanged drug were estimated at various times in serum and urine, over 24 h and 48 h, respectively. Cefpirome concentrations were determined using both high pressure liquid chromatography (HPLC) and a microbiological assay. The measurements obtained were compared by linear distribution independent regression, and were found to be equivalent. A linear relationship between dose and AUC00 (r = 0.96) for both HPLC and microbiological assay was demonstrated for the doses tested (0.25 g to 2.0 g). The biological half-life (t1/2,beta) was determined by fitting a two-compartment open model to the data: t1/2,beta was about 2 h (HPLC, median values) and was not relevantly dose dependent. A general twice daily dosing will be recommended for the treatment of infections. Clinically relevant high concentrations of unchanged cefpirome were detected in urine already after the lowest dose (0.25 g) for about 12 h, and after the highest dose (2.0 g) for at least 24 h. General tolerance was good, only slight temporary taste disturbances immediately after injection were claimed by one volunteer after both 0.5 g and 1.0 g doses and by four volunteers receiving 2.0 g of cefpirome; however, no counter-measures were needed.

Renal tolerance of cefpirome (HR 810), a new cephalosporin antibiotic.

An open study was carried out in ten healthy, male volunteers in order to investigate the renal tolerance of cefpirome (HR 810), a new cephalosporin antibiotic. Subjects received a single dose of 1.0 g of cefpirome and then repeated doses of 1.0 g of cefpirome twice daily for five days. Urine was collected in several fractions during the study and the urine excretion, excretions of creatinine, N-acetyl-beta-D-glucosaminidase, gamma glutamyltransferase, alanine aminopeptidase and lactate dehydrogenase were calculated in 12-hour fractions. Serum creatinine (using an enzymatic method), beta 2-microglobulin concentrations and creatinine clearance were also determined. Based on the findings of these renal enzymes, renal tolerance was good. This was also confirmed by creatinine clearance calculations and follow-up of serum beta 2-microglobulin levels. Cefpirome showed good renal tolerance without any signs of nephrotoxicity in this study with the methods used.

Pharmacokinetic interaction study with ramipril and digoxin in healthy volunteers.

Coadministration of captopril has been shown to increase serum digoxin concentration. The effects of ramipril, a new angiotensin converting enzyme inhibitor, on serum digoxin concentration after multiple dosing were studied in 12 healthy volunteers. All subjects were receiving steady-state digoxin medication (0.5 mg daily), and ramipril (5 mg daily) was coadministered for 14 days. Serum digoxin concentration was measured repeatedly before, during and up to 1 week after ramipril coadministration at 8 a.m. (trough values) and on selected trial days at 11 a.m., 3 hours after the morning medication. Simultaneously, blood levels of ramipril and its active metabolite diacid were determined. Volunteers were followed closely for side effects and for changes in blood pressure, heart rate and electrocardiogram. Safety pharmacology included serial determination of sodium, potassium, serum glutamic oxaloacetic transaminase, creatinine and a full blood count. Mean serum digoxin concentration was not significantly influenced by ramipril coadministration with trough levels of 0.90 +/- 0.24 before, 0.93 +/- 0.38 during and 0.82 +/- 0.33 ng/ml after ramipril medication. The increase in serum digoxin concentration 3 hours after the morning dose was also not significantly affected by ramipril. Serum levels of ramipril and its diacid showed a wide range of variation. Mean serum potassium increased by 0.3 mmol/liter during ramipril coadministration with development of symptomless hyperkalemia (6.0 mmol/liter) in 1 subject. The only other side effect possibly related to ramipril was a dry cough in 1 subject. Both drugs were well tolerated. Ramipril showed no significant influence on serum digoxin levels in healthy volunteers.

Piretanide in the treatment of essential hypertension. A double-blind comparison versus placebo.

In a randomized, double-blind parallel group study the 24-hour hypotensive effect of piretanide and its influence on biochemical variables were compared with those of placebo in patients with mild to moderate essential hypertension. Sixty patients entered the study, all of whom met the inclusion criteria (RRdiast between 95 and 120 mmHg). There was no drop-out during the study, so that the results of all 60 patients were statistically analysed. Piretanide produced a significant reduction of both systolic and diastolic blood pressure over 24 hours which was evident at four weeks and was maintained and further enhanced over the ensuing trial period. A mean maximal fall (at 12 weeks) of 10.7% (BPdiast supine) was observed. Placebo tablets did not produce any clinically relevant changes in systolic blood pressure, whereas a slight decrease was seen in diastolic blood pressure. This blood pressure reduction was significantly less in the placebo group than in the piretanide group at the end of the study (weeks 10 and 12). Dose doubling was needed in 13 of the 30 patients in the piretanide group, whereas as many as 20 out of 30 patients needed dose doubling in the placebo group. Pulse rate did not change relevantly during the trial in either group. A slight reduction in body weight was observed in the piretanide group. The mean values of serum potassium and sodium showed a slight decrease but remained within the normal range during the study period. A small increase in serum phosphorus was noted. None of these changes required any specific measures.(ABSTRACT TRUNCATED AT 250 WORDS)

Lipoprotein lipids and apoproteins during beta-blocker administration: comparison of penbutolol and atenolol.

Serum lipoprotein lipid and apoprotein concentrations were determined in 21 hypertensive men during administration of two beta-blockers, penbutolol or atenolol, for 6 months preceded by a 4 week placebo period. Post-heparin plasma lipoprotein lipase and hepatic lipase activities were also measured. There was a trend to an increase of triglyceride and VLDL triglyceride concentrations during penbutolol administration, but the changes were not significant. Penbutolol also increased the total cholesterol by 11% at 3 months (mainly due to increase of VLDL cholesterol), but this effect diminished at 6 months. Atenolol did not cause any significant change in the total cholesterol but increased HDL cholesterol by 7% at 1 month, the change being due to rise of the HDL3. The HDL3 accounted also for a significant decrease of HDL cholesterol seen in the men receiving penbutolol at 6 months. HDL2 cholesterol as well as the LDL/HDL2 cholesterol ratio remained unchanged in both groups. Neither drug consistently influenced the postheparin plasma lipase activities or the serum apoprotein A or B concentrations. In contrast to an earlier study the results suggest that the clinically most important HDL subfraction, the HDL2, remains unaffected during treatment with beta-blockers.

Cefodizime penetration into skin suction blister fluid following a single intravenous dose.

Cefodizime pharmacokinetics was investigated, evaluating drug concentrations in serum, skin suction blister fluid (SBF), saliva and urine in six healthy male subjects who were administered a 1-g dose intravenously. Serum levels in five subjects can be described according to a two-compartment open model; terminal half-life is 181 +/- 14 min. Volume of distribution (Vd beta) amounts to 15.3 +/- 1.61, serum clearance to 59 +/- 6 ml/min, renal clearance to 33 +/- 3 ml/min. Of the administered dose, 54% is renally excreted unchanged within 27 h. Unbound drug fraction in serum is 19.0% and in SBF 38.4%. Thus renal clearance of free cefodizime amounts to 172 ml/min, Vdss to 68.9 l (free drug). Whereas cefodizime has not been detected in saliva samples, SBF concentration 3-9 h post administration parallel serum levels, amounting to 40% of the respective serum concentration. At 9 h, unbound cefodizime concentrations in SBF amount to 1.4 +/- 0.4 micrograms/ml, this value being well above the MIC90% values of many clinically relevant bacteria.

Echocardiographic determination of left ventricular haemodynamics following acute and chronic administration of frusemide (Lasix) to patients with heart failure.

Twenty patients (8 females) with NYHA class II symptoms of chronic left ventricular heart failure completed a study to investigate the hemodynamic effects of intravenous and oral frusemide. Echocardiography indicated that frusemide 20 mg intravenously produces a transient undesired hemodynamic effect in the prediuretic phase without any influence on the patient's clinical symptoms. Once diuresis is established the hemodynamic conditions are reversed and there is an improvement in cardiac function. There is no evidence of a direct positive inotropic effect of the drug. Repeated oral dosing with frusemide 40 mg/day for 3 weeks produced an improvement in cardiac hemodynamics particularly during the first 2 weeks of treatment. The possible underlying mechanisms for these observations are discussed.

The effects of piretanide capsules on blood pressure during ergometric and isometric work loads in patients with mild to moderate essential hypertension.

A single-blind study was carried out in 22 out-patients with mild to moderate hypertension to investigate the effects of piretanide capsules on systolic and diastolic blood pressure during standardized ergometric and isometric exercise. After a 4-week run-in period on placebo, patients received 1 capsule (6 mg) once daily for 6 weeks. If diastolic pressure was normalized (less than 95 mmHg), this dosage was continued for a further 6 weeks; patients whose blood pressure remained high after the initial 6 weeks received 1 capsule twice daily for a further 6 weeks. Significant reductions in blood pressure (9.2% for systolic, 14.6% for diastolic) were measured after 12-weeks' treatment during maximum ergometric work load exercise; during isometric exercise the reductions were 8.1% and 12.4%, respectively. The pulse-pressure product (a parameter indicating myocardial oxygen consumption), calculated for maximum ergometric exercise, was also significantly reduced by 8.8% after 12-weeks' active drug treatment. Serum levels of potassium, creatinine, urea, uric acid and cholesterol showed no clinically relevant changes during treatment. Side-effects definitely or probably associated with piretanide were observed in 13 patients. These, however, were generally mild and did not lead to interruption of piretanide treatment. Transient polyuria was reported by 5 patients during the first 2 weeks of active drug treatment; only 3 patients reported mild polyuria after 12 weeks of active drug treatment. The beneficial effect of piretanide especially on systolic blood pressure during exercise was in marked contrast effect of piretanide especially on systolic blood pressure during exercise was in marked contrast to the lack of such an effect reported during treatment with thiazide and other thiazide-like diuretics.

Pharmacodynamic and pharmacokinetic study of oral and intravenous penbutolol.

The present study was done to establish the dose-response relationships for effects on heart rate and systolic and diastolic blood pressure, tolerance and plasma disappearance kinetics after large intravenous and oral doses of penbutolol. Twelve healthy volunteers were randomly allocated to receive penbutolol (n = 8) or placebo (n = 4) in this single blind, placebo-controlled investigation. The degree of beta-blockade was measured by standarized exercise tests at work loads selected to produce a heart rate of 150/min without treatment. Penbutolol was given as single i.v. doses of 3, 6 and 12 mg and as 40, 80 and 120 mg once daily for one week, measurements being made 2 and 24 h after the last dose. Penbutolol i.v. did not influence the resting heart rate but it did reduce resting systolic blood pressure in a non-dose dependent manner. Exercise heart rate and systolic pressure were lowered by all the intravenous doses. All oral doses of penbutolol lowered exercise heart rate and systolic blood pressure to the same extent. The reductions in exercise tachycardia was still present after 24 h. After i.v. administration t1/2 was approximately 1.2 h and the volume of distribution was 32-421. All doses were well tolerated.